Despite SARS-CoV-2 being a “novel” coronavirus, several studies suggest that detection of anti-spike IgG early in infection may be attributable to the amplification of humoral memory responses against seasonal hCoVs in severe COVID-19 patients. In this study, we examined this concept by characterizing anti-spike IgG from a cohort of non-hospitalized convalescent individuals with a spectrum of COVID-19 severity. We observed that anti-spike IgG levels positively correlated with disease severity, higher IgG cross-reactivity against betacoronaviruses (SARS-CoV-1 and OC43), and higher levels of proinflammatory Fc gamma receptor 2a and 3a (FcγR2a & FcγR3a) activation. In examining the levels of IgG targeting betacoronavirus conserved and immunodominant epitopes versus disease severity, we observed a positive correlation with the levels of IgG targeting the conserved S2’FP region, and an inverse correlation with two conserved epitopes around the heptad repeat (HR) 2 region. In comparing the levels of IgG targeting non-conserved epitopes, we observed that only one of three non-conserved immunodominant epitopes correlated with disease severity. Notably, the levels of IgG targeting the receptor binding domain (RBD) were inversely correlated with severity. Importantly, targeting of the RBD and HR2 regions have both been shown to mediate SARS-CoV-2 neutralization. These findings show that, aside from antibody (Ab) targeting of the RBD region, humoral memory responses against seasonal betacoronaviruses are potentially an important factor in dictating COVID-19 severity, with anti-HR2-dominant Ab profiles representing protective memory responses, while an anti-S2’FP dominant Ab profiles indicate deleterious recall responses. Though these profiles are masked in whole antigen profiling, these analyses suggest that distinct Ab memory responses are detectable with epitope targeting analysis. These findings have important implications for predicting severity of SARS-CoV-2 infections (primary and reinfections), and may predict vaccine efficacy in subpopulations with different dominant antibody epitope profiles.

中文翻译：

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针对季节性冠状病毒的体液免疫反应可预测 SARS-CoV-2 尖峰靶向、FcγR 激活和相应的 COVID-19 疾病严重程度的效率

尽管 SARS-CoV-2 是一种“新型”冠状病毒，但几项研究表明，在感染早期检测到抗尖峰 IgG 可能归因于重症 COVID-19 患者中针对季节性 hCoV 的体液记忆反应的放大。在这项研究中，我们通过表征来自具有一系列 COVID-19 严重程度的非住院康复者队列的抗尖峰 IgG 来检验这一概念。我们观察到，抗尖峰 IgG 水平与疾病严重程度、对 β冠状病毒（SARS-CoV-1 和 OC43）的更高 IgG 交叉反应性以及更高水平的促炎 Fc γ 受体 2a 和 3a（FcγR2a 和 FcγR3a）激活呈正相关。在检查针对β冠状病毒保守和免疫优势表位的 IgG 水平与疾病严重程度的关系时，我们观察到与靶向保守 S2'FP 区域的 IgG 水平呈正相关，而与七肽重复 (HR) 2 区域周围的两个保守表位呈负相关。在比较靶向非保守表位的 IgG 水平时，我们观察到三个非保守免疫优势表位中只有一个与疾病严重程度相关。值得注意的是，靶向受体结合域 (RBD) 的 IgG 水平与严重程度呈负相关。重要的是，针对 RBD 和 HR2 区域均已被证明可以介导 SARS-CoV-2 中和。这些发现表明，除了针对 RBD 区域的抗体 (Ab) 外，针对季节性 β 冠状病毒的体液记忆反应可能是决定 COVID-19 严重程度的重要因素，抗 HR2 显性抗体谱代表保护性记忆反应，而抗 S2'FP 显性抗体谱表明有害回忆反应。尽管这些谱在整个抗原谱中被掩盖了，但这些分析表明，通过表位靶向分析可以检测到不同的 Ab 记忆反应。这些发现对于预测 SARS-CoV-2 感染（原发性和再感染）的严重程度具有重要意义，并可能预测具有不同显性抗体表位特征的亚群中的疫苗效力。